Adumbration; A history lesson

“History is more or less bunk. It’s tradition. We want to live in the present and the only history that is worth a tinker’s damn is the history we make today” (Henry Ford: Chicago Tribune, 1916)

OR

“What is past is prologue”

(Shakespeare: The Tempest, 1610)

Over three centuries apart, these oft cited quotations set the boundary markers of a ubiquitous dichotomy of viewpoints over the benefit of exploring or ignoring the past to explain the present.

“Adumbration” is an ideal semantic companion to this dispute between the man who invented the Edsel and the world’s most famous poet and playwright. It is a fickle word plagued by ambiguous meanings and variable usage. It derives (OED) from the Latin, “umbrare” – shadow coupled to “an” – fore. Hence it is defined both as “foreshadowing” or “overshadowing” an idea or a discovery, faintly predicting or disparaging the event.

In manifold writings Robert Merton created a subspecialty of sociological enquiry surrounding scientific discoveries, the behavior of scientists and the dubious role of adumbration in that process. (Merton, 1967, 1968 a, 1968 b, 1969). Within this framework I will examine one scientific discovery in which I played a key role and discuss its relevance to contemporary psychopharmacology. A full description of this process is available (Blackwell et al, 1967) and its relationship to the process of discovery is described elsewhere (Ayd & Blackwell, 1971).

This essay will set the stage with a barebones outline of the discovery itself before an historical dissection of the manner in which it was foretold in the literature accompanied by reflections about adumbration and other contemporary implications.

In 1962, aged 28, I began as a first year registrar (resident) at the Institute of Psychiatry (Maudsley Hospital) in London. I had completed my medical training at Guy’s Hospital as a House Officer followed by a 6 month neurology rotation at the Whittington Hospital in North London. I had already published several articles showing an interest in research but, devoid of the desired Membership in the Royal College of Physicians (MRCP), I was relegated to the “B stream” on Lindford Rees’ Unit at the Bethlem Royal Hospital. Lindford was a founding member of the CINP and had engaged in early research on the tricyclic antidepressants which were just beginning to compete with the MAO inhibitors. Iproniazid (Marsilid) had been marketed since 1958 but was quickly overtaken by tranylcypromine (Parnate) from 1960, popular both alone and combined with a small dose of Stelazine as Parstelin.

During neurology training I worked under a senior registrar who had published a letter to the Lancet about a patient who suffered a subarachnoid hemorrhage while taking Parnate; taking a drug history in every patient admitted in such cases was mandatory but unproductive. Until, several months later, I was eating lunch in the Maudsley cafeteria and overheard registrars at the next table discussing a young woman who had just suffered a subarachnoid bleed. Had she been taking Parnate I asked? She had! Soon afterwards, chatting with my G.P. he told me of two similar cases seen in a matter of weeks. Eager to “publish or perish” I fired off a letter to the Lancet suggesting this serious, potentially fatal side effect, might be commoner than appeared. (Blackwell, 1963). There had been six similar letters in the previous 20 months describing a syndrome of hypertension associated with a pounding occipital headache and, more rarely, a subarachnoid hemorrhage.

Two weeks later I received a letter from a hospital pharmacist in Nottingham, G.E.F. Rowe, who had read the Lancet and recognized the symptoms as identical to those his wife had experienced twice after eating cheese. He described the episodes in detail in a letter that concluded:

“Could there be a link between the effects and the amino acids of cheese? No effects are caused by butter or milk. Although treatment has continued, no further episodes have occurred. If cheese is indeed the factor it could perhaps explain the sporadic nature of the incidence of the side effect. I hope my comment will be of some use to you in your investigations.”

My first response to this remarkably prescient description was skepticism tinged with humor, until I shared the letter with the manufacturer’s representative, Gerald Samuels, of Smith Kline and French. He had heard of similar reports including one in a patient taking tryptophan and tranylcypromine in a research study. Perhaps I should look into the composition of cheese? Instead, together with a fellow female resident, we took Parnate for a week before eating cheddar cheese from the cafeteria and measuring our blood pressure. Nothing happened. But when I checked the hospital menu for the night the Maudsley patient had suffered her hemorrhage I discovered she had eaten a cheese flan for supper.

Not sure what to do next, chance favored the prepared mind (Louis Pasteur). Moonlighting for a local family practitioner (the commanding officer of my reserve army field ambulance) I received a call one evening from a distraught husband whose wife was experiencing a sudden severe occipital headache. She was taking Parnate and had eaten a cheese sandwich for supper. I jumped into my car to do a home visit and found her in the middle of a hypertensive crisis which subsided without treatment while I took her blood pressure. Determined to gather further cases I was unsure of where to look. But not long afterwards, working late at the Maudsley, I ran into the duty registrar (Bob Kendall) on his way to the psychotherapy unit. He had been called to see two women in adjacent beds both taking Parnate, suffering from sudden severe headaches, having returned from the cafeteria after eating cheese.

Convinced now of the relationship between eating cheese and suffering a hypertensive crisis I wondered why we had not experienced this in our self-experimentation with Parnate. Perhaps the interaction was due to some propensity peculiar to patients? Boldly, and by today’s standards perhaps unethically, I asked a female inpatient taking Parnate (Mrs. Borrett) and her husband if she would be willing to eat cheese while I took her blood pressure. After I explained the risks and steps I would take to counter any major increase in pressure they agreed. She ate cheese and I sat by her bedside for two hours uneventfully before leaving to see patients on another ward. Within ten minutes my pager went off: the nurse caring for my patient asked, “Could she give her aspirin for headache?” I rushed back to the unit, found her in the midst of a hypertensive crisis that subsided without complications or treatment within 45 minutes.

Within 9 months of my original letter to the Lancet I had collected 12 patients taking an MAOI, mostly Parnate, of whom 8 had eaten cheese prior to the event. The publication in the Lancet (Blackwell 1963) included a graph of the blood pressure recordings in my volunteer patient. The article produced a rapid response. A patient wrote to say she had known of the association for some time but “doctors laughed at the idea”. The Medical Director of Smith, Kline & French dismissed my findings as “unscientific and premature”. Another doctor had treated hundreds of patients with an MAOI and never seen a severe headache although headache occurs at least once weekly in a third of the population. This spectrum of responses illustrates the dual meanings of adumbration; from faintly predicting to critical disparagement.

It is not uncommon for a serious side effect to be discovered several years after a drug is approved for marketing. In this instance it was unusually long. 8 years elapsed between the first use of an MAOI to treat depression and discovery of the tyramine interactions during which time 40 fatal cases occurred. This hiatus is generally attributable to the inadequacy of short term double blind studies needed to obtain FDA approval. Sample sizes are small and populations highly selected with treatment lasting only long enough to determine statistical significance compared to placebo but inadequate to reveal rare or unusual side effects. It is interesting to note however that among the earliest studies of iproniazid, (Marsilid) in the treatment of tuberculosis (Ogilvie, 1955) 4 out of 42 patients suffered hypertension and headache but a cause was never pursued.

There were other reasons why recognition of the causative factor was delayed. It is a truism that “everyone eats cheese”. Eating cheese is common but the side effect was rare while even those who suffered an attack ate cheese again with impunity serving to obscure a cause and effect relationship. An analogy can be made to sex and pregnancy. The first is common but the second is relatively rare; there are many intervening variables between the act and the outcome.

Doubt, disparagement and skepticism were short lived after the publication of the Lancet article. Within weeks a team of researchers at a London teaching hospital ate Gorgonzola cheese and identified tyramine with spectroscopy in their body fluids. (Asatoor, Levi & Milne, 1963).

It would soon become my responsibility to identify other factors producing a variable response to eating cheese while taking an MAOI. Suddenly in the limelight, I was promoted to the Professorial Unit at the Maudsley and came under the eagle eye of Sir Aubrey Lewis. After observing my work for several months he took me aside and asked was I “by any chance in psychoanalysis?” Approving of my denial he offered me the chance to learn about research in a pharmacology fellowship under the mentorship of Ted Marley. For two years I worked in a World War II Nissan hut on the margins of the campus surrounded by cages of cats, rats and baby chicks until I completed the work necessary to explain the mechanism of action of the interaction between MAO inhibitors and tyramine containing foods.

Not long after starting my research Sir Aubrey, who was multilingual and a Greek scholar told me he “thought Hippocrates had something to say about cheese.” I found a book on Greek Medicine (Brock 1929) to discover the doubts Hippocrates expressed; “It is not enough to know that cheese is a bad article of food in that it gives pain to anyone eating it in excess, but what sort of pain, and why, and with what principle in man it disagrees…” This quotation became an apt prologue to the Doctoral dissertation presented at Cambridge University at the conclusion of research answering those questions. (Blackwell, 1966).

Working with the National Institute for Research in dairying we learned that the tyramine content of cheese varies considerably depending on the amino acid composition and the abundance or activity of decarboxylating bacteria that convert tyrosine to tyramine. A myth developed that mostly mature and “smelly” cheeses were at fault but our research on multiple samples of identically appearing cheddar cheese (including several that had caused hypertension) varied widely in tyramine content; pieces of cheddar cheese were like cans of garbage – identical on the outside but differing in their content. (Blackwell & Mabbitt, 1965). Excavating the literature revealed that tyrosine was first identified in cheese and named after the Greek word for it, tyros. (Liebig 1846). Later on tyramine was also discovered in cheese and in the early twentieth century physiologists discovered it was a hypertensive agent (Dale & Dixon, 1909).

Two years later an internist developing the sphygmomanometer injected tyramine into adults and children to calibrate the instrument (Findlay, 1911). In the process he expressed concern that rapid rises in blood pressure might cause a cerebral hemorrhage. Observations on patients taking an MAOI and suffering food induced hypertension revealed several factors determining the outcome. Development of severe throbbing occipital headache occurs when there is a large rapid increase in blood pressure (approximately 50mm or more in less than 10 minutes). Ingestion and absorption of small amounts of tyramine produced less dramatic increases in blood pressure and were asymptomatic. Even if headache occurred the blood pressure usually returned to normal within 45 minutes without treatment. These factors are responsible for the unlikelihood that most people experiencing the symptoms of a hypertensive crisis would be seen by a physician.

Another factor influencing the occurrence and severity of an interaction was the MAOI prescribed its dosage, and the regimen. Although cases were reported with all the MAOI Parnate was by far the most common drug incriminated and early on it was known as “Parnate headache.” In part this may have been contributed to by the fact that in a study on Maudsley outpatients (Blackwell & Taylor, 1967) it was the most often prescribed and most effective of the MAOI before the discovery of the tyramine interaction. This was probably due to the drug’s therapeutic index and pharmacologic properties. The starting therapeutic dose produced sufficient inhibition of intestinal MAO to allow ingress of tyramine while the drug’s amphetamine like structure and effects likely contributed a release of stored nor-epinephrine, augmenting the effect of tyramine. Metabolic studies on a patient taking a less potent MAOI, phenelzine (Nardil) revealed that blood pressure responses to graduated amounts of tyramine in Marmite were influence by dosage, duration of treatment and proximity to an antecedent dose of the drug. (Blackwell, Marley, Price & Taylor 1967).

Monoamine oxidase was named tyramine oxidase after its first know substrate (Hare, 1928) and then renamed monoamine oxidase. Its distribution and purpose in the gut was first described by Blaschko to include the denial of access to the circulation of amines present in foods (Blaschko, 1952). This knowledge and speculation was made only 3 years before an MAO was first used to alter the brain chemistry of patients suffering from depression.

The fear that toxic substances absorbed from the gut might cause serious and unpleasant symptoms has a long history up to the present preoccupation with probiotics and colonic “regularity” (Blackwell, 1966). In the late 19th century the German scientist Metchnikoff suggested the colon was a “putrefying sac” from which toxic amines in foods might be absorbed into the bloodstream. Queen Victoria’s surgeon, Sir Arbuthnot Lane, subscribed to this belief and made a fortune removing the colon for constipation. In 1906 Bernard Shaw wrote the play, “The Doctor’s Dilemma”, which parodied this practice with a character named Sir Colenso Ridgeon who removed an offending organ, the “nuciform sac”. The controversy surrounding this topic became the subject of a conference convened by the Royal Society of Medicine in 1913 during which headaches were among the offending symptoms and cheese a potential foodstuff. These events were contemporaneous with the discovery of the hypertensive properties of tyramine and its associated dangers discussed earlier.

If, as this case study suggests, scientific discovery can be predicted or disparaged (adumbration) it is not surprising that controversy can arise over related aspects of the process. Robert Merton writes about several (Merton, 1968 a & b). These include conflicts over priority (who made the original or major contribution?), the tendency of scientists to deny an interest in claiming priority (Freud included), the willingness of leading scientists to accept prestigious awards overlooking the contribution of junior colleagues (the “Mathew effect”) all of which are abetted by selective forgetting (“cryptomnesia”).

Two examples in the modern history of neuropsychopharmacology are the 1964 Lasker Award to Nathan Kline for the introduction of MAOI into psychiatry and the 1978 Lasker Award to Sol Snyder and others for discovery of opiate receptors. In both cases junior colleagues claimed their contributions were overlooked.

The cheese story is not immune from such problems. Two people had reasons to feel slighted. GEF Rowe deserves full credit for the first documented mention of a link between cheese and sudden severe headache while taking an MAOI. My first article describing this interaction (Blackwell, 1963) did not make attribution but every subsequent publication has done so. My recollection is that I also sent him copies of all papers we published at the conclusion of the research but this is contested.

The second person, Gerald Samuels, complained vociferously and continuously. Three years after we first met and he encouraged me to pursue the contents of cheese, we met again when he visited me in his role as the pharmaceutical representative for Smith Kline & French. I learned how bitter he was for not being acknowledged in any of our publications. Feeling his resentment was justified and wishing to make amends I suggested we write a joint article describing his role and contribution. This was published with Gerald as first author in the Journal of Hospital Medicine, (Samuels & Blackwell, 1968). Shortly afterwards he came to dinner in my home and presented me with a cheese board engraved with the words, “Everyone Eats Cheese”. I assumed we were reconciled but about fifteen years later he published an angry letter in the British Journal of Psychiatry again complaining bitterly. He had contacted Mr.Rowe and alleged he was also aggrieved and had never heard from me. I decided not to respond, feeling that there was nothing further I could do to assuage such deep seated and long-lasting emotions.

Carefully construed there are a plethora of allies to whom I am grateful in the discovery process. In this instance to mentors and colleagues who assisted or encouraged my enquiries; Lindford Rees, Gerald Russell who welcomed me onto his Metabolic Unit and David Taylor, fellow registrar and lifelong friend. To Sir Aubrey Lewis who opened the door to research. To Ted Marley who endured my clumsy efforts at animal research and pled my ability for doctoral work to Cambridge University. To the female colleague and two women patients who volunteered to be experimental subjects. To the microbiologist who analyzed cheese and educated us in food science. To the scientists at another hospital who identified tyramine in cheese and gave the story credibility.

Still, in addition to adumbration, perhaps there are other ways to think about the lessons learned from the MAOI-tyramine story. Was the field of psychiatry well served by the discovery? Certainly lives were saved – perhaps 5 or so patients a year at the peak of MAOI prescribing. But we had learned how to deal with this side effect by avoiding tyramine containing foods; perhaps too many and indiscriminately as recently suggested (McCable et al, 2006). But still the drugs were too useful to be quickly abandoned. Parnate use declined abruptly, followed over a few years by almost no significant prescribing of MAOIs after the SSRI antidepressants appeared. Eager for the field to move on this transition occurred before we had fully defined the features of patients who benefitted. The vague term “atypical depression” was proposed and included increased sleep and appetite perhaps combined with features of apathy, lack of motivation, decreased libido and self- blame. These sound like the same features that for many years were treated by outpatient use of amphetamines, properties that tranylcypromine shared but for which a comparison was never made.

What might the pharmaceutical industry learn from this story? Industry is always eager to identify a putative “mechanism of action” as part of persuasive advertising. Interfering with an enzyme, receptor system or neuro-transmitter should always raise the question of where else that entity exists in the body, what function it fulfills and the likely consequences of tampering with it. Manifestly this was not so, judged by the speed with which the first article was brushed aside. But the information was all there in plain sight on the pages of credible scientific journals, waiting to be read.

Based on this history of adumbration it would be reasonable to assume that a competent and ethical pharmaceutical company would search the literature to find all the known possible pharmacological effects that might result from the drug they planned to promote including preclinical research in animals and cautious Phase 1 studies in humans followed by specific anticipatory data collection relevant to the risks in Phase 2.

POSTSCRIPT

“Those who cannot remember the past are condemned to repeat it”

(George Santayana 1863-1952)

In 1998 Celebrex (celecoxib) was marketed by Pfizer close on the heels of Vioxx (rofecoxib) already on its way to being a blockbuster. Both drugs belonged in the category of non-steroidal ant-inflammatory drugs (NSAIDs) for the treatment of pain and inflammation in arthritis. Both claimed to be safer and more effective than earlier drugs in the same widely used category. They share a mechanism of action on the enzyme cycloxygenase-2 (Cox-2). Like monoamine oxidase the enzyme exists in two forms, is widely distributed throughout the body with manifold functions.

Sales of Celebrex reached $3.1 billion in 2001 and around that time my joints and spine began to ache and groan from the burden imposed by twenty years of playing rugby and pushing in the scrum. A hip replacement seemed inevitable but in the honeymoon of this new drug my internist thought it was worth a try.

One week after starting treatment my face erupted in exfoliative dermatitis but, unaware this was a side effect, I continued until a few days later I suddenly became breathless while climbing the stairs at home. Alarmed, though not in pain, my wife drove me to an emergency room where my blood pressure was 210/170 mm Hg. Normotensive throughout my sixty-five years I was on the verge of left ventricular failure. After inserting an I/V and a dose of mild sedative the blood pressure fell to near normal over two hours. It has remained mildly elevated since, responding to conservative treatment. The package insert made no mention of cardiovascular complications so I informed the FDA and the manufacturer. The FDA was silent but Pfizer, knowing I was a physician, mailed several reassuring publications implying the absence of any similar problems.

I was naturally struck by the similarity between this drug reaction, without the headache, and my experience almost forty years earlier with the MAOI tyramine story. I even toyed with the idea of self- experimentation to test the hypothesis but wisely declined. I only had to wait 3 more years for the truth to unfold.

In 2004 Merck withdrew rofecoxbid (Vioxx) from the market. The story is told by NPR on the internet (Prakash & Valentine 2007).

In 1999 Merck, concerned that Vioxx, like other NSAIDs, might cause gastrointestinal bleeding, launched an 8000 patient study comparing Vioxx to Naproxen, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR). The company appointed a Data and Safety Monitoring Board (DSMB) chaired by Michael Weinblatt (Brigham & Women’s Hospital) who owned $73,000 in Merck stock and earned $5000 a day as a consultant.

During 2000 the results of VIGOR were submitted to the FDA and published in the NEJM but the journal article omitted 3 cases of heart attack along with other cardiovascular events. Reanalysis of the data by independent researchers cast doubt on the VIGOR conclusion that the increase in cardiovascular risk might be due to Naproxen protecting the heart rather than Vioxx damaging it. Between 2002 and 2004 further epidemiological studies confirmed Vioxx’s increased cardiovascular risk.

In September 2004 Merck withdrew Vioxx from the market after it had been used by an estimated 20 million Americans. Subsequent research in the Lancet estimated that 88,000 Americans had heart attacks while taking the drug and more than 8,000 died.

Further FDA analysis of the data on Vioxx revealed that cardiovascular events began shortly after starting the drug and remained long after the drug was stopped.

In 2007 Merck agreed to pay $4.85 billion to end thousands of law suits coupled with a statement that it did not admit fault.

After Vioxx was withdrawn Pfizer benefited from an increase in its sales cut short by further bad data and an FDA “black box” warning in 2005 that all NSAIDs shared comparable cardiovascular risks. For a two year period they suspended direct advertising to the public but resumed in magazines in 2006 and television in 2007 where their “For a Body in Motion” commercials continue to run frequently, casting a “quality of life” glow and drowning out dire mandatory warnings with distracting happy visual images.

In 2009 Scott Reuben (Chief of acute pain at Bayside Medical Center, Springfield, Mass) revealed that 21 studies he conducted on Celebrex and other NSAIDs were fabricated to exaggerate analgesic effects.

The current package labelling for Celebrex conveys the following information: “As with all NSAIDs, Celebrex can lead to the onset of new hypertension or worsening of previous hypertension, either of which may contribute to the increased incidence of cardiovascular events. Blood pressure should be closely monitored with all the NSAIDs.”

With the wisdom of hindsight, history and adumbration it seems paradoxical that one drug which provoked hypertension for which the cause was removed, should almost perish while another still thrives making $2 billion or more a year while its risks remain intact. Worse still, it feels unjust and unscientific!

The word “unscientific” is used advisedly, providing yet another lesson. The difference between the Parnate and Celebrex stories is that between commerce and science and the conflicts of interest this creates. Both involved unanticipated and potentially lethal cardiovascular effects caused by drugs in widespread use for several years. By reason of how each was discovered Parnate fell into the academic domain of medicine, Celebrex into the commercial. Academic motivations involve both personal and social/ethical goals; publishing scientific papers, obtaining advanced degrees, promotion or tenure, and recognition within one’s field. Traditionally also, doctors are sworn to doing good with minimal harm to patients. The target of my investigations was to explain the mechanism of action involved to the benefit of my career as well as making MAOI safer to use and even, perhaps, saving a few lives.

In the case of Parnate, once tyramine was identified the truth was out. Ted Marley and I were invited to SKF headquarters to meet their pharmacologist. We made an agreement to publish the results of our animal research on the mechanism of action simultaneously. Some months later the editor of the Lancet informed us that SKF had reneged and submitted their results unilaterally. We were given a month to submit our own research; working day and night we met the deadline and both papers were published back to back (Blackwell & Marley 1964), (Natoff,1964).

With Celebrex the story was different. No attempt was made to study or explain the mechanism of action. But like SKF’s initial response Pfizer’s entire effort was devoted to denying and then minimizing the problem. The unanticipated nature of the side effect, its severity and frequency, created liability and provoked litigation. To the extent physicians were involved one falsely exaggerated the drug’s efficacy while another participated in minimizing its risk; both benefited financially.

Once serious side effects are recognized by the FDA and ‘black box’ warnings mandated companies use their vast profits to stifle law suits without admitting culpability. Industry views this as “the cost of doing business” which is built into the high price of the drug in question. The only evidence of penitence or accountability on the part of Pfizer was a brief hiatus in advertising directly to the consumer, soon resumed with gusto; observing the letter of FDA law but skirting its spirit. Now that all the official warnings are in place Pfizer no longer has culpability for the drug it sells. Side effects become the responsibility of the physician who prescribes the drug and the patient who is beguiled or bemused into taking it.

Note: For a fuller discussion of “Conflict of interest” see the “Controversies” program on the INHN.Org website.